The long-term objective is to provide effective treatment for patients with severe, and presently untreatable, consequences of hyperuricemia. These patients are either hypersensitive to the xanthine oxidase inhibitor allopurinol, refractory to conventional hypouricemic therapy, or use of allopurinol would interfere with necessary therapy for organ graft rejection or leukemia. As a result, these patients suffer severe, painful, and disabling tophaceous gout, and they are at high risk of developing renal failure. Based on the view that the metabolic disorder is due to a species-wide inborn error of uric acid breakdown due to lack of urate oxidase (uricase), and the recent discovery that humans express a mutated mRNA for the enzyme urate oxidase (uricase), we request support to continue the pre-clinical investigation of polyethyleneglycol (PEG) modified mammalian uricase as a potentially nonimmunogenic treatment for hyperuricemia. Our specific aims are I) to use biochemical and recombinant DNA methods to engineer PEG-modified recombinant mammalian urate oxidase and investigate its activity, circulating life and immunogenicity; 2) we will investigate the efficacy of the PEG-uricase in an animal model of uric acid renal obstruction; 3) we will develop GMP methods for producing mammalian PEG-uricase for use in clinical trials. PROPOSED COMMERCIAL APPLICATION: Commercial application is for the control of severe hyperuricemia and its consequences, including gout and renal failure, in patients for whom conventional therapy is ineffective or contraindicated. PEG-uricase would be developed as an Orphan Drug to treat patients allergic to allopurinol (estimated to be about 2% of patients receiving that drug), and organ transplant patients who develop severe gout. The advantages of the PEG-mammalian uricase over fungal uricase currently used in Europe are a prolonged circulating life and reduced immunogenicity.